The delivery of macromolecular proteins to animals is complicated by the need for delivery devices which will maintain the bioactivity of the protein prior to, during, and after administration to the animal. Merely exposing macromolecular proteins to aqueous environments causes the large proteins to form precipitates and aggregates which destroy the bioactivity and therefore the usefulness of the protein. Also, hydrolytic reactions resulting from "wetting" the proteins may produce bio-inactive products which reduce the in vivo effectiveness of the protein.
Prior art methods for overcoming this problem have included encapsulating the macromolecular proteins in polymer-coated tablets which limit the ingress of water, pressing the macromolecular proteins into pellet compositions which control the release of the protein by limiting the surface area of the pellet and therefore the amount of water that has access to the protein, placing the macromolecular proteins in porous devices which limit the ability of water to enter the device and the ability of the protein to exit the device, and the like. Patents and other references describing these methods are voluminous and well known in the art.
Prior art particularly relevant to the present invention include U.S. Pat. No. 4,177,256 which discloses a drug delivery device in which discrete depots containing an osmotic solute are dispersed in a polymer body such that the polymer completely surrounds the depots. The polymer body is formed such that the defined surface area that is exposed to the environment is controlled. Water enters the polymer at the surface, saturates the depots, and generates an osmotic pressure within the depots which causes them to burst and release their contents to the environment. Only the depots near the surface are affected initially; the water penetrates the polymer body over time and ruptures depots that are encased deeper in the body. The prolonged release is achieved by the size and shape of the polymeric body; by controlling the surface area and the time it takes the water from the environment to reach the depots. The depots are uniform in size and composition and rupture within a relatively short time after being exposed to the water.
U.S. Pat. No. 3,247,066 discloses a water-soluble beadlet which comprises a core of medicant surrounded by a water-permeable polymer coating. When the beadlet is placed in an aqueous environment, water enters the beadlet and causes the core to expand. The expanding core "bursts" the coating and releases the medicant in the core. The beadlet is designed to be used within the gastrointestinal tract, have a release time of 8-12 hours, and is designed to deliver low molecular weight organics, antibiotics, and the like, particularly compounds such as aspirin, barbiturates, and similar low molecular weight organic molecules. Additionally, a preferred embodiment of the disclosed invention comprises a plurality of small beads having different surface areas, coating thicknesses, coating types, and the like which are administered in a pharmaceutical carrier such as a soft shelled capsule. The invention is not, however, designed to deliver macromolecular proteins for prolonged periods via a non-gastrointestinal route.
Ueda et al., Proceed. Intern. Symp. Control. Rel. Bioact. Mater., Vol. 15, page 450 (1988) disclose a time-controlled explosion system (TES) for delivering drugs in vivo. Ueda states that any pattern of drug release can be obtained by combining spheres with different coating thicknesses. However, Ueda's TES system is not designed to meet the special requirements for delivering macromolecular proteins. Also, Ueda's device has an "onion-like" structure; a sucrose bead is surrounded by the drug, the drug-bead is surrounded by a swelling agent, and the drug-bead-swelling agent is surrounded by a polymer.
Because of the problems associated with prior controlled release delivery devices for macromolecular proteins, there exists a continuing need for new controlled release delivery devices which control the manner and timing of delivery while maintaining the stability and bioactivity of the macromolecular proteins when the device is administered to an animal.